Pluripotent stem cell‐based screening identifies CUDC‐907 as an effective compound for restoring the in vitro phenotype of Nakajo‐Nishimura syndrome,STEM CELLS Translational Medicine

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Pluripotent stem cell‐based screening identifies CUDC‐907 as an effective compound for restoring the in vitro phenotype of Nakajo‐Nishimura syndrome
STEM CELLS Translational Medicine ( IF 5.4 ) Pub Date : 2020-10-14 , DOI: 10.1002/sctm.20-0198
Naoya Kase ₁ , Madoka Terashima ₁ , Akira Ohta ₂ , Akira Niwa ₁ , Fumiko Honda-Ozaki _{1,

3} , Yuri Kawasaki ₁ , Tatsutoshi Nakahata ₂ , Nobuo Kanazawa ₄ , Megumu K Saito ₁

Affiliation

Nakajo‐Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in the PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)‐derived NNS disease model that reproduces several inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein‐1 (MCP‐1) and interferon gamma‐induced protein‐10 (IP‐10). Here we performed high‐throughput compound screening (HTS) using this PSC‐derived NNS model to find potential therapeutic candidates and identified CUDC‐907 as an effective inhibitor of the release of MCP‐1 and IP‐10. Short‐term treatment of CUDC‐907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post‐transcriptional. These findings suggest that HTS with PSC‐derived disease models is useful for finding drug candidates for autoinflammatory diseases.

中文翻译：

基于多能干细胞的筛选鉴定出 CUDC-907 是恢复 Nakajo-Nishimura 综合征体外表型的有效化合物

Nakajo-Nishimura 综合征 (NNS) 是由PSMB8纯合突变引起的自身炎症性疾病基因。全身性皮质类固醇的给药是部分有效的，但持续治疗会导致严重的副作用。我们之前建立了一种多能干细胞 (PSC) 衍生的 NNS 疾病模型，该模型可再现多种炎症表型，包括单核细胞趋化蛋白-1 (MCP-1) 和干扰素γ诱导蛋白-10 (IP-10) 的过量产生。在这里，我们使用这种 PSC 衍生的 NNS 模型进行了高通量化合物筛选 (HTS)，以寻找潜在的治疗候选物，并将 CUDC-907 鉴定为 MCP-1 和 IP-10 释放的有效抑制剂。CUDC-907 的短期治疗不会在治疗浓度内诱导细胞死亡，并且对原代患者细胞也有效。进一步分析表明抑制作用是转录后的。

更新日期：2020-10-14

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